JPH0679B2 - Process for producing optically active benzyl alcohol compound - Google Patents

Description

The present invention relates to a method for producing an optically active benzyl alcohol compound. More specifically, the general formula [In the Formula, X represents a fluorine atom, a chlorine atom, or a bromine atom, R is a hydrogen atom, a C1-C18 alkyl group, a C2-C18 alkenyl group, a C2-C18 alkynyl group, carbon. C 1-4 halogen-substituted alkyl group, C 2-4 halogen-substituted alkenyl group, C 2-4 halogen-substituted alkynyl group, C 1-8 alkoxyl group, C 2-8 alkenyloxy group Alternatively, it represents an alkynyloxy group having 2 to 8 carbon atoms. ] To the ester of the (R, S) -form α-cyano-benzyl alcohol compound represented by Arthrobacter, Chromobacterium, Cydudomonas, Aspergillus, Mucor, Alcaligenes, Achromobacter, Rhizopus Belongs to any one of the genera and (R,
An esterase derived from a microorganism having the ability to act on an (S) -form α-cyano-benzyl alcohol compound to preferentially asymmetrically hydrolyze an ester of the (S) -form α-cyano-benzyl alcohol compound to pH 7 is used. The following formula is used to asymmetrically hydrolyze the ester to give a compound of the general formula [In the formula, X has the same meaning as described above. ] The (S) -enriched α-cyano-benzyl alcohol compound represented by the formula (1) and the enantiomer of the (S) -enriched (S) -enantiomer represented by the general formula (II) The present invention relates to a method for producing an optically active α-cyano-benzyl alcohol compound.

[Industrial application field]

The α-cyano-benzyl alcohol compound represented by the above general formula (II) is known as a novel alcohol component of a group of ester compounds called so-called synthetic pyrethroids having excellent insecticidal activity.

[Problems to be solved by the invention]

Since the α-cyano-benzyl alcohol compound has an asymmetric carbon atom at the α-position, there are two types of optical isomers, and the insecticidal effect as an ester is α-S of the (S) -form.
The -cyano-benzyl alcohol compound is far superior to the corresponding R-form. Therefore, the (R, S) -form of the α-cyano-obtained by a conventional synthetic chemical production method is used.
It has been desired to develop a technique for optically resolving a benzyl alcohol compound by an industrially advantageous method to obtain its (S) -form.

[Conventional technology]

By the way, the α-cyano-benzyl alcohol compound is
Since it is an unstable compound, its optical resolution is not easy, and the presently known method for optical resolution of the alcohol currently requires complicated steps and expensive optically active reagents.

[Means for solving problems]

The present inventors can be an industrially advantageous production method (S)-
As a result of repeated studies to find out a process for producing the α-cyano-benzyl alcohol compound represented by the above general formula (II), the racemic compound, that is, the (R, S) -form represented by the above general formula (I) An ester of an α-cyano-benzyl alcohol compound is used as a starting material, and is biochemically asymmetrically hydrolyzed to obtain an α-cyano-benzyl represented by the general formula (II), which is rich in the (S) -form and is optically active. It was found that an alcohol compound and an ester of its antipode can be effectively resolved, and further various studies were conducted to complete the present invention.

That is, the present invention acts on the ester of the (R, S) -form α-cyano-benzyl alcohol compound represented by the above general formula (I) to form the ester of the (S) -form α-cyano-benzyl alcohol compound. Esterase produced by a microorganism having the ability to preferentially asymmetrically hydrolyze (a esterase in the present invention means esterase in a broad sense including lipase), and (R, S) -form α-cyano- The benzyl alcohol compound ester is allowed to act at a pH of 7 or less,
By asymmetrically hydrolyzing this, the (S) -enriched optically active α-cyano-benzyl alcohol compound represented by the general formula (II) and the enantiomer of the α-cyano-benzyl alcohol compound are separated (S). The present invention provides a process for producing an optically active α-cyano-benzyl alcohol compound represented by the general formula (II), which is rich in form.

Next, the method of the present invention will be described in detail.

The esterase-producing microorganism used in the method of the present invention acts on the ester represented by the general formula (I) in the (R, S) -form to preferentially deactivate the ester of the alcohol compound in the (S) -form. Any microorganism can be used regardless of its genus as long as it is a microorganism that produces esterase having the ability to undergo simultaneous hydrolysis. Examples of such microorganisms include Arthrobacter (Ar
throbacter) genus, Alcaligenes genus,
Achromobacter genus, Pseudomonas genus Chromobacte
Rium, Rhizopus, Muco
r) and microorganisms belonging to the genus As-pergillus. Among them, from the viewpoint of hydrolytic ability and optical purity of the obtained optically active α-cyano-benzyl alcohol compound represented by the general formula (II), Arthrobacter, Alcaligenes, Achromobacter, Pseudomonas, Chromobacter Esterases produced by microorganisms belonging to the genus Urum are preferred.

Specific examples of the microorganisms belonging to the above-mentioned genus of microorganisms include the following bacterial cells.

(1) Arthrobacter simplex IF-3530 Arthrobacter simplex (2) Alcaligenes faecalis
IF-12669 Alcaligenes faecalis (3) Achromobacter sp. (4) Pseudomonas fluorescens (5) Chromobacterium viscosum ATCC-6918 Chromobacterium viscosum (6) IFO-4737 Rhizopus chinensis (7) Mucor Javanicus IFO-4572 Mucor javanicus (8) Aspergillus var. Asper IFO-5324 Aspergillus var. Asper
) Or American Type Culture Collection (ATCC)
It is stored in and can be obtained from this preservation organization.

Some esterases of microbial origin are commercially available, and this commercially available enzyme can also be used for the purpose of the present invention.

Examples of commercially available enzymes that can be used in the present invention include those shown below.

In carrying out the present invention, the compound represented by the general formula (R,
The asymmetric hydrolysis of the S) -form ester represented by the general formula (I) is carried out by a culture solution obtained by culturing the above-mentioned microorganism, a culture solution, a suspension of bacterial cells or a treated product thereof such as a crude esterase or a purified esterase. And an aqueous solution containing
It is carried out by mixing the S) -form ester and stirring or shaking. If necessary, a non-ester type surfactant may be added. It is also possible to immobilize the enzyme and use it.

At this time, the reaction temperature is suitably 10 to 65 ° C, particularly preferably 20 to 50 ° C. The reaction time is usually 3 to 48 hours, but the reaction time can be shortened by increasing the reaction temperature or using an enzyme having high activity.

It is important to keep the reaction pH below pH 7, pH 3.5 to pH
It is preferable to keep it in the range of 6.0.

Further, it is desirable to control the pH at a constant level by using a buffer solution or the like to prevent the pH from being lowered by an organic acid such as acetic acid generated by hydrolysis. As the buffer solution, either an inorganic acid salt or an organic acid salt can be used.

The working concentration of the ester represented by the general formula (I) of the (R, S) -form as the substrate is 1 to 80 w / w% with respect to the reaction solution.
, Preferably 5 to 40 w / w%.

After carrying out the asymmetric hydrolysis reaction in this way, the optically active α-cyano-benzyl alcohol represented by the general formula (II) liberated by operations such as stationary separation, solvent extraction, and column chromatography. The compound and unreacted ester of the antipode alcohol compound are separated and recovered.

As such a separation and recovery operation, for example, the reaction-terminated liquid is extracted with an organic solvent such as ether, benzene, or toluene, and the extract is subjected to column chromatography using silica gel or the like to obtain cyclohexane-ether (95: 5). ) It is possible to separate and obtain the free optically active α-cyano-benzyl alcohol compound represented by the general formula (II) and the unreacted enantiomer ester by elution with a solution.

The unreacted organic carboxylic acid ester thus separated and recovered can be racemized by bringing it into contact with a basic compound such as ammonia, pyridine or triethylamine, and used again as a raw material for the method of the present invention.

Further, in the present invention, it is used as a raw material (R,
The S) -form of the ester represented by the general formula (I) can be obtained by a conventional method for producing an ester, for example, the (R, S) -form α-cyano-benzyl alcohol compound represented by the general formula (II). I
II) [In the formula, R ₁ is a hydrogen atom, an alkyl group having 1 to 18 carbon atoms,
C2-C18 alkenyl group, C2-C18 alkynyl group, C1-C4 halogen-substituted alkyl group, C2-C4 halogen-substituted alkenyl group, or C2-carbon
Represented by a halogen-substituted alkynyl group of ~ 4. ] A method of reacting an organic carboxylic acid halide (for example, acid chloride, acid bromide) or an acid anhydride represented by, or an organic carboxylic acid halide (for example, acid chloride, acid bromide) represented by the above general formula (III) And general formula (IV) [In the formula, X has the same meaning as described above. ] A method of reacting an aldehyde compound represented by and sodium cyanide,
Alternatively, the (R, S) -form α-is represented by the general formula (II).
General formula (V) for cyano-benzyl alcohol compounds [In the formula, R ₂ is an alkyl group having 1 to 8 carbon atoms, and 2 to 8 carbon atoms.
Represents an alkenyl group or an alkynyl group having 2 to 8 carbon atoms. ] It can be easily obtained by a method of reacting a chloroformate represented by

The organic carboxylic acid represented by the general formula (III),
For example, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, isoceric acid, caproic acid, capric acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, or halogen substitution thereof. The fatty acid having 2 to 12 carbon atoms or the carbon having 1 chlorine atom or bromine atom at its α-position is taken into consideration in view of easiness of handling, optical purity of the reaction product by asymmetric hydrolysis and the like. Halogen-substituted fatty acids of the formulas 1 to 4 are preferable, and acetic acid, propionic acid, monochloroacetic acid, and monobromoacetic acid are more preferable from the viewpoint of easy availability and economy.

Further, as the chloroformic acid ester represented by the general formula (V), methyl chlorocarbonate, ethyl chlorocarbonate, chlorocarbonate propyl and the like are preferable from the viewpoint of easy availability and economical efficiency.

The method of the present invention is, in addition to the ester represented by the general formula (I), α-cyano- represented by the general formula (II) as a substrate.
It can also be applied when using a half ester of an organic dicarboxylic acid of a benzyl alcohol compound.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Examples 1-8 Acetic acid ester of (R, S) -α-cyano-3- (4-chlorophenoxy) -4-fluorobenzyl alcohol
2.0 g and 40 mg of each esterase described in Table 1 were added to 15 ml of a 0.2 M acetate buffer (pH 4.0), and the mixture was reacted at 40 ° C. with stirring. After reacting for 24 hours, the reaction product was extracted with toluene. The extract was analyzed by high performance liquid chromatography (HPLC) [Lichrosorb RP-18, methanol-water (6: 4), 254 mm, uv detection], and α-cyano-3- (4-chlorophenoxy) -4-fluoro The hydrolysis rate was calculated from the peak area ratio of benzyl alcohol to acetic acid ester.

After concentrating the extract, silica gel column chromatography was performed, and cyclohexane-ethyl ether (9
5: 5) After elution with a solution to separate and remove unreacted acetic acid ester of α-cyano-3-chlorophenoxy) -4-fluorobenzyl alcohol, a further small amount (10 ⁻⁵ %)
Elution with methanol containing paratoluenesulfonic acid, free α-cyano-3- (4-chlorophenoxy) -4-
Fluorobenzyl alcohol was obtained.

10 mg of the obtained free α-cyano-3- (4-chlorophenoxy) -4-fluorobenzyl alcohol was dissolved in 1 ml of toluene, and equimolar (S)-(+)-2-
The chloride of (4-chlorophenyl) -isobutyric acid and pyridine were added and reacted to obtain α-cyano-3- (4-chlorophenoxy) -4-fluorobenzyl alcohol.
(S)-(+)-2- (4-chlorophenyl) -isocubic acid diastereomer, and optical isomer analysis by gas chromatography (column: DCQE-1, 2.5 m, column temperature: 250 ° C) It was

The results are shown in Table 1.

Examples 9 to 18 Using 2.0 g of various (R, S) -form α-cyano-3-phenoxybenzyl alcohol compounds described in Table 2 as substrates, 0.2 g of this and 40 mg of each esterase described in Table 2 were used. Add to 15 ml of M-concentration acetate buffer (pH 4.0) 4
The reaction was carried out with stirring at 0 ° C. Thereafter, the same operations as in Examples 1 to 8 were performed. The results are shown in Table 2.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location (C12P 41/00 C12R 1:38) (C12P 41/00 C12R 1:66) (C12P 41/00 (C12R 1: 785) (C12P 41/00 C12R 1:05) (C12P 41/00 C12R 1: 025) (C12P 41/00 C12R 1: 845)

Claims (6)

[Claims] 1. A general formula [In the Formula, X represents a fluorine atom, a chlorine atom, or a bromine atom, R is a hydrogen atom, a C1-C18 alkyl group, a C2-C18 alkenyl group, a C2-C18 alkynyl group, carbon. C 1-4 halogen-substituted alkyl group, C 2-4 halogen-substituted alkenyl group, C 2-4 halogen-substituted alkynyl group, C 1-8 alkoxyl group, C 2-8 alkenyloxy group Alternatively, it represents an alkynyloxy group having 2 to 8 carbon atoms. ] To the ester of the (R, S) -form α-cyano-benzyl alcohol compound represented by Arthrobacter, Chromobacterium, Cydudomonas, Aspergillus, Mucor, Alcaligenes, Achromobacter, Rhizopus Belongs to any one of the genera and (R,
An esterase derived from a microorganism having the ability to act on an ester of a (S) -form α-cyano-benzyl alcohol compound to preferentially asymmetrically hydrolyze the ester of a (S) -form α-cyano-benzyl alcohol compound At pH 7 or lower to asymmetrically hydrolyze the ester to give a compound of the general formula [In the formula, X has the same meaning as described above. ] The (S) -enriched α-cyano-benzyl alcohol compound represented by the formula: and the enantiomer of the enantiomer of the (S) -enriched (S) -enriched A process for producing an optically active α-cyano-benzyl alcohol compound. 2. An esterase which belongs to the genus Arthrobacter, the genus Alcaligenes, the genus Achromobacter, the genus Pseudomonas or the genus Chromobacterium, and is of the above-mentioned (R, S) -form α-cyano-benzyl alcohol compound. The method according to claim 1, which is an esterase derived from a microorganism, which has the ability to act on an ester to preferentially asymmetrically hydrolyze an ester of an (S) -form α-cyano-benzyl alcohol compound. 3. In the ester represented by the general formula (I), the substituent R is an alkyl group having 1 to 11 carbon atoms, an alkenyl group having 2 to 11 carbon atoms, an alkynyl group having 2 to 11 carbon atoms, Alkyl group having 1 to 4 carbon atoms having one chlorine atom or bromine atom at the α-position, alkenyl group having 2 to 4 carbon atoms having one chlorine atom or bromine atom at the α-position, and α- The process according to claim 1 or 2, which is an alkynyl group having 2 to 4 carbon atoms or an alkoxyl group having 1 to 8 carbon atoms having one chlorine atom or bromine atom at the position. 4. The ester represented by the general formula (I), wherein the substituent R is a methyl group, an ethyl group, a monochloromethyl group, a monobromomethyl group, a methoxy group, an ethoxy group or a propoxy group. The manufacturing method according to claim 2 or 3. 5. The asymmetric hydrolysis reaction is carried out from pH 3.5 to 6.0.
The manufacturing method according to claim 1, claim 2, claim 3, or claim 4, which is performed within the range. 6. The production method according to claim 1, claim 2, claim 3, claim 4 or claim 5, wherein the asymmetric hydrolysis reaction is carried out at 20 ° C to 50 ° C.